title: Loss of metabotropic glutamate receptor 2 escalates alcohol consumption.
abstract: Identification of genes influencing complex traits is hampered by genetic heterogeneity, the modest effect size of many alleles, and the likely involvement of rare and uncommon alleles. Etiologic complexity can be simplified in model organisms. By genomic sequencing, linkage analysis, and functional validation, we identified that genetic variation of Grm2, which encodes metabotropic glutamate receptor 2 (mGluR2), alters alcohol preference in animal models. Selectively bred alcohol-preferring (P) rats are homozygous for a Grm2 stop codon (Grm2 *407) that leads to largely uncompensated loss of mGluR2. mGluR2 receptor expression was absent, synaptic glutamate transmission was impaired, and expression of genes involved in synaptic function was altered. Grm2 *407 was linked to increased alcohol consumption and preference in F2 rats generated by intercrossing inbred P and nonpreferring rats. Pharmacologic blockade of mGluR2 escalated alcohol self-administration in Wistar rats, the parental strain of P and nonpreferring rats. The causal role of mGluR2 in altered alcohol preference was further supported by elevated alcohol consumption in Grm2 (-/-) mice. Together, these data point to mGluR2 as an origin of alcohol preference and a potential therapeutic target.
authors.affiliation: Laboratories of Neurogenetics and Clinical and Translational Studies and Section on Synaptic Pharmacology, Laboratory for Integrative Neuroscience, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892.
authors.forename: Zhifeng
authors.initials: Z
authors.lastname: Zhou
authors.forename: Camilla
authors.initials: C
authors.lastname: Karlsson
authors.forename: Tiebing
authors.initials: T
authors.lastname: Liang
authors.forename: Wei
authors.initials: W
authors.lastname: Xiong
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Kimura
authors.forename: Jenica D
authors.initials: JD
authors.lastname: Tapocik
authors.forename: Qiaoping
authors.initials: Q
authors.lastname: Yuan
authors.forename: Estelle
authors.initials: E
authors.lastname: Barbier
authors.forename: Austin
authors.initials: A
authors.lastname: Feng
authors.forename: Meghan
authors.initials: M
authors.lastname: Flanigan
authors.forename: Eric
authors.initials: E
authors.lastname: Augier
authors.forename: Mary-Anne
authors.initials: MA
authors.lastname: Enoch
authors.forename: Colin A
authors.initials: CA
authors.lastname: Hodgkinson
authors.forename: Pei-Hong
authors.initials: PH
authors.lastname: Shen
authors.forename: David M
authors.initials: DM
authors.lastname: Lovinger
authors.forename: Howard J
authors.initials: HJ
authors.lastname: Edenberg
authors.forename: Markus
authors.initials: M
authors.lastname: Heilig
authors.forename: David
authors.initials: D
authors.lastname: Goldman
mesh_terms: D000428:Alcohol Drinking / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D018388:Codon, Terminator; D003433:Crosses, Genetic; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D018698:Glutamic Acid / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D051381:Rats; D017208:Rats, Wistar; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D013569:Synapses / Q000235:genetics / Q000378:metabolism; D009435:Synaptic Transmission / Q000187:drug effects / Q000235:genetics*
chemical_list: D018388:Codon, Terminator; D018691:Excitatory Amino Acid Antagonists; D018094:Receptors, Metabotropic Glutamate; C108822:metabotropic glutamate receptor 2; D018698:Glutamic Acid
keywords: gene identification; selectively bred lines